An interactive and multidisciplinary team of investigators at the Ireland Comprehensive Cancer Center at University Hospitals of Cleveland (UHC) and Case Western Reserve University (CWRU) have effectively and creatively designed a variety of mechanistically-based Phase I clinical trials. The sustenance of our Phase I drug development effort is rooted in very strong laboratory-based scientific expertise, ability to develop and incorporate pharmacodynamic endpoints into our studies, expert pharmacokinetic analytic capability, and the use of novel phase I study designs to address mechanism of action or proof of biologic effect of a given drug. Our approach to phase I development of anticancer agents is to engage our scientists, develop novel tissue-based and radiological imaging monitoring strategies, and take advantage of pharmacologic expertise to better understand and develop a specific drug. Each of these strategies has been capitalized upon in the cooperative development of novel anticancer agents with the NCI's Cancer Therapy Evaluation Program (CTEP) during the past grant cycle. Our group has provided scientific leadership to CTEP for the development of 4 agents during this period including O6-benzylguanine (BG), rebeccamycin analog, bryostatin 1, and SU5416 among others. The clinical development of these 4 agents clearly demonstrates that linking our CTEP-sponsored Phase I studies with the Cancer Center's scientific expertise is a robust strategy for early clinical trials of new anticancer agents with phase I emphasis. The early clinical development of new anticancer agents we will investigate over the coming grant cycle will be greatly facilitated by two interrelated recently NIH-funded initiatives at our own center. These programs complement NCI's cohesive and integrated program in drug discovery and clinical development. The first initiative is a P20 award (1P20 CA91710-01), to establish a In Vivo Cellular and Molecular Imaging Center (ICMIC), in response to RFA-CA-99-04.Investigators on this project have framed a pilot study of topotecan, combining radiopharmaceutical labeling and PET scan expertise to monitor tumor tissue kinetics of the anticancer agent. The other initiative is a supplement to our current U01 cooperative entitled, "Kinase Target Assessment in Colon Cancer" as part of the NCI's Interdisciplinary Research Teams for Molecular Target Assessment in response to RFA-CA-00-001. In this project, investigators are developing immunohistochemical techniques using phosphoform-specific antibodies to determine the frequency and activation status (phosphorylation) of kinase targets [e.g., epidermal growth factor receptor (EGFR)] in clinical samples. These initiatives allow us to generate data on drug effect and the unique opportunity to optimize schedules of administration. The Phase I program is also a founding member of the CTEP-sponsored Organ Dysfunction Working Group (ODWG) and has taken agents it has developed in the phase I setting into early phase II trials as part of the CWRU - University of Pittsburgh - Henry Ford consortia. It is the intent of this application to continue to build on this strong clinical translational research program and, more importantly, to provide a resource for the cooperative evaluation of scientifically directed phase I trials of promising anticancer agents available from the NCI drug screening program or referred to NCI from other sources. The Developmental Therapeutics Program at the Cancer Center looks forward to renewing its collaborative relationship with CTEP and other investigators in pursuit of the development of new anticancer agents with Phase I emphasis. [unreadable] [unreadable] [unreadable]